Zebrafish as a Model for Fetal Alcohol Spectrum Disorders

In this review, we will discuss zebrafish as a model for studying mechanisms of human fetal alcohol spectrum disorders (FASDs). We will overview the studies on FASDs so far and will discuss with specific focus on the mechanisms by which alcohol alters cell migration during the early embryogenesis including blastula, gastrula, and organogenesis stages which later cause morphological defects in the brain and other tissues. FASDs are caused by an elevated alcohol level in the pregnant mother’s body. The symptoms of FASDs include microcephaly, holoprosencephaly, craniofacial abnormalities, and cardiac defects with birth defect in severe cases, and in milder cases, the symptoms lead to developmental and learning disabilities. The transparent zebrafish embryo offers an ideal model system to investigate the genetic, cellular, and organismal responses to alcohol. In the zebrafish, the effects of alcohol were observed in many places during the embryo development from the stem cell gene expression at the blastula/gastrula stage, gastrulation cell movement, morphogenesis of the central nervous system, and neuronal development. The data revealed that ethanol suppresses convergence, extension, and epiboly cell movement at the gastrula stage and cause the failure of normal neural plate formation. Subsequently, other cell movements including neurulation, eye field morphogenesis, and neural crest migration are also suppressed, leading to the malformation of the brain and spinal cord, including microcephaly, cyclopia, spinal bifida, and craniofacial abnormalities. The testing cell migration in zebrafish would provide convenient biomarkers for the toxicity of alcohol and other related chemicals, and investigate the molecular link between the target signaling pathways, following brain development.

Riboceine Rescues Auranofin-Induced Craniofacial Defects in Zebrafish

Craniofacial abnormalities are a common group of congenital developmental disorders that can require intensive oral surgery as part of their treatment. Neural crest cells (NCCs) contribute to the facial structures; however, they are extremely sensitive to high levels of oxidative stress, which result in craniofacial abnormalities under perturbed developmental environments. The oxidative stress-inducing compound auranofin (AFN) disrupts craniofacial development in wildtype zebrafish embryos. Here, we tested whether the antioxidant Riboceine (RBC) rescues craniofacial defects arising from exposure to AFN. RBC rescued AFN-induced cellular apoptosis and distinct defects of the cranial cartilage in zebrafish larvae. Zebrafish embryos exposed to AFN have higher expression of antioxidant genes gstp1 and prxd1, with RBC treatment partially rescuing these gene expression profiles. Our data suggest that antioxidants may have utility in preventing defects in the craniofacial cartilage owing to environmental or genetic risk, perhaps by enhancing cell survival.

Bifid Tongue and Cleft Palate: A Rare Congenital Malformation

Background: Congenital bifid tongue without other craniofacial abnormalities is a very rare malformation. Here, we discuss a case of the bifid tongue with cleft palate, reported in a 7-month-old girl with no other syndromes or craniofacial abnormalities. Case Reports: This case report described a 7-month-old girl with an anterior bifid tongue, separated medially by a soft, solitary sublingual mass measuring 3 cm x 2 cm in size. There was also an associated incomplete cleft palate. A soft solitary mass measuring 2 cm x 2 cm in size was also seen within the cleft palate. Results: Computed facial tomography (CT) revealed a midline hard palate defect with an intact alveolar process of the maxilla. Pedunculated cystic lesion suspected with epulis was noted to arise on premaxillary alveolar mucosa. Excision of the tongue and hard palate mass and repair of the bifid tongue were done. Summary: Congenital bifid tongue with a cleft is a very rare malformation with different variations. Early surgical intervention is critical to prevent speech impairment and swallowing disorders. A multidisciplinary approach, including well-planned staged operations and rehabilitation, is important to achieve favorable outcomes.

Detecting Hearing Loss in Infants With a Syndrome or Craniofacial Abnormalities Following the Newborn Hearing Screen

Purpose The current Joint Committee on Infant Hearing guidelines recommend that infants with syndromes or craniofacial abnormalities (CFAs) who pass the universal newborn hearing screening (UNHS) undergo audiological assessment by 9 months of age. However, emerging research suggests that children with these risk factors are at increased risk of early hearing loss despite passing UNHS. To establish whether earlier diagnostic audiological assessment is warranted for all infants with a syndrome or CFA, regardless of screening outcome, this study compared audiological outcomes of those who passed UNHS and those who referred. Method A retrospective analysis was performed on infants with a syndrome or CFA born between July 1, 2012, and June 30, 2017 who participated in Queensland, Australia's state-wide UNHS program. Results Permanent childhood hearing loss (PCHL) yield was higher among infants who referred on newborn hearing screening (51.20%) than in those who passed. Nonetheless, 27.47% of infants who passed were subsequently diagnosed with hearing loss (4.45% PCHL, 23.02% transient conductive), but PCHL was generally milder in this cohort. After microtia/atresia, the most common PCHL etiologies were Trisomy 21, other syndromes, and cleft palate. Of the other syndromes, Pierre Robin sequence featured prominently among infants who passed the hearing screen and were subsequently diagnosed with PCHL, whereas there was a broader mix of other syndromes that caused PCHL in infants who referred on screening. Conclusion Children identified with a syndrome or CFA benefit from early diagnostic audiological assessment, regardless of their newborn hearing screening outcome.

A Novel Frameshift Mutation in The NHS Gene Causes Nance-Horan Syndrome in a Chinese Family

Background:Nance-Horan syndrome (NHS), also known as cataract-tooth syndrome, is a rare X-linked genetic disorder characterized by congenital cataract as well as dental and craniofacial abnormalities caused by mutations in the NHS gene.In this study,we describe a Chinese family with a frameshift mutation in NHS associated Nance-Horan syndrome, thus expanding the mutational spectrum of this gene.Methods:Four members (including three patients) had their ocular bodies examined in the presence of congenital cataracts featuring dental and craniofacial abnormalities. DNA samples of family members were extracted from peripheral venous blood, and known pathogenic genes of congenital cataracts were panel sequenced.Results:In the proband, a novel frameshift mutation (c.1694_1697delGAATinsCATTCG) was identified in the NHS gene. Sanger sequencing of family members verified that the mutation completely co-segregated with the disease in the pedigree.Conclusion:The congenital cataract family was diagnosed as having Nance-Horan syndrome (NHS), and the NHS frameshift mutation was determined to cause the disease in this family. This is a novel NHS gene mutation that has not been reported previously.

Case Report: Pansynostosis, Chiari I Malformation and Syringomyelia in a Child With Frontometaphyseal Dysplasia 1

Frontometaphyseal dysplasia 1 (FMD1) is a rare otopalatodigital spectrum disorder (OPDSD) that is inherited as an X-linked trait and it is caused by gain-of-function mutations in the FLNA. It is characterized by generalized skeletal dysplasia, and craniofacial abnormalities including facial dysmorphism (supraorbital hyperostosis, hypertelorism, and down-slanting palpebral fissures). The involvement of the central nervous system in patients with OPDSD is rare. Herein, we present the case of a 12-year-old boy with facial dysmorphism, multiple joint contractures, sensorineural hearing loss, scoliosis, craniosynostosis, and irregular sclerosis with hyperostosis of the skull. Brain and whole-spine magnetic resonance imaging revealed Chiari I malformation with extensive hydrosyringomyelia from the C1 to T12 levels. Targeted next-generation sequencing identified a hemizygous pathologic variant (c.3557C>T/p.Ser1186Leu) in the FLNA, confirming the diagnosis of FMD1. This is the first report of a rare case of OPDSD with pansynostosis and Chiari I malformation accompanied by extensive syringomyelia.